Therapeutic efficacy of a novel non-peptide αvβ3 integrin antagonist for pathological retinal angiogenesis in mice.

αvβ3 integrin has been reported as a promising therapeutic target for angiogenesis. In the present study, we tested the antiangiogenic activity of 3-[3-(6-guanidino-1-oxoisoindolin-2-yl) propanamido]-3-(pyridin-3-yl) propanoic acid dihydrochloride (GOPPP), a novel non-peptide αvβ3 antagonist. Both human umbilical vein endothelial cells (HUVECs) and a mouse model of oxygen-induced retinopathy (OIR) were investigated separately. HUVEC adhesion, proliferation, migration, ERK1/2 and Akt phosphorylation were assessed. C57BL/6 mice were used for the studies in the OIR model. After exposure to 75% oxygen from postnatal day (PD) 7 to PD12, the mice were returned to room air, and GOPPP was intravitreally administered on PD12. Retinal neovascularization was evaluated on PD17. Hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) protein levels and ERK1/2 phosphorylation were determined by Western blot analysis of retina proteins. GOPPP significantly inhibited the pro-angiogenic effects of vitronectin on HUVECs, including adhesion, proliferation, and migration, and inhibited ERK1/2 and Akt phosphorylation. Retinal neovascularization in the OIR model was significantly suppressed by intravitreal administration of 50 ng GOPPP. The pro-angiogenic factors HIF-1α and VEGF induced by hypoxia were significantly inhibited by GOPPP in OIR mice. GOPPP administration also inhibited ERK1/2 phosphorylation in the OIR model. These results indicate that GOPPP, a novel αvβ3 integrin antagonist, may have potential for the treatment of pathological retinal angiogenesis.